Apparatus and methods for sealing a vascular puncture

ABSTRACT

A sealant for sealing a puncture through tissue includes a first section, e.g., formed from freeze-dried hydrogel, and a second section extending from the distal end. The second section may be formed from PEG-precursors including PEG-ester and PEG-amine, e.g., in an equivalent ratio of active group sites of PEG-ester/PEG-amine greater than one-to-one, e.g., such that excess esters may provide faster activation upon contact with physiological fluids and enhance adhesion of the sealant within a puncture. At least some of the precursors remain in an unreactive state until exposed to an aqueous physiological environment, e.g., within a puncture, whereupon the precursors undergo in-situ cross-linking to provide adhesion to tissue adjacent the puncture. For example, the PEG-amine precursors may include the free amine form and the salt form. The free amine form at least partially cross-links with the PEG-ester and the salt form remains in the unreactive state in the sealant before introduction into the puncture.

RELATED APPLICATION DATA

The present application is a continuation-in-part of co-pendingapplication Ser. No. 13/354,278, filed Jan. 19, 2012, which claimsbenefit of U.S. provisional application Ser. No. 61/434,412, filed Jan.19, 2011, the entire disclosures of which are expressly incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates generally to sealants, apparatus, andmethods for sealing punctures in a body, and more particularly, toapparatus and methods for sealing a vascular puncture extending throughtissue to a blood vessel.

BACKGROUND

Apparatus and methods are known for accessing a patient's vasculaturepercutaneously, e.g., to perform a procedure within the vasculature, andfor sealing the puncture that results after completing the procedure.For example, a hollow needle may be inserted through a patient's skinand overlying tissue into a blood vessel. A guide wire may be passedthrough the needle lumen into the blood vessel, whereupon the needle maybe removed. An introducer, procedural, or femoral sheath may then beadvanced over the guide wire into the vessel, e.g., in conjunction withor subsequent to one or more dilators. A catheter or other device may beadvanced through the introducer sheath and over the guide wire into aposition for performing a medical procedure. Thus, the introducer sheathmay facilitate accessing and/or introducing various devices into thevessel, while minimizing trauma to the vessel wall and/or minimizingblood loss.

Upon completing the procedure, the device(s) and introducer sheath maybe removed, leaving a puncture extending between the skin and the vesselwall. To seal the puncture, external pressure may be applied to theoverlying tissue, e.g., manually and/or using sandbags, until hemostasisoccurs. This procedure, however, may be time consuming and expensive,requiring as much as an hour of a medical professional's time. It isalso uncomfortable for the patient, and may require the patient toremain immobilized in the operating room, catheter lab, or holding area.In addition, a risk of hematoma exists from bleeding before hemostasisoccurs.

Various apparatus and methods have been suggested for sealing vascularpunctures resulting from such procedures, such as those disclosed inU.S. Pat. Nos. 7,316,704, 7,331,979, 7,335,220, and 7,806,856, and U.S.Publication Nos. 2007/0231366, 2008/0082122, 2009/0088793, 2009/0254110,2010/0168789, 2010/0274280, and 2010/0280546. The entire disclosures ofthese references are expressly incorporated by reference herein.

For example, the MATRIX™ product included two synthetic polyethyleneglycol (“PEG”) polymer powders that were mixed with appropriate buffersand injected through a femoral sheath at an arteriotomy site, e.g., asdisclosed in U.S. Pat. No. 7,316,704. The Mynx® Vascular Closure Deviceis another system for sealing vascular punctures, e.g., as disclosed inone or more of the references identified above, such as U.S. Pat. No.7,335,220.

Accordingly, apparatus and methods for sealing a puncture through tissuewould be useful.

SUMMARY

The present invention is directed to apparatus and methods for sealing apuncture in a body. More particularly, the present invention is directedto sealants for sealing a puncture through tissue, and to methods formaking such sealants. In addition, the present invention is directed toapparatus and methods for providing temporary or permanent hemostasiswithin a puncture extending through tissue, and/or to apparatus andmethods for delivering a sealant into a percutaneous puncture extendingfrom a patient's skin to a blood vessel or other body lumen.

In accordance with one embodiment, a sealant is provided for sealing apuncture through tissue that includes a first section including aproximal end, a distal end, and a cross-section sized for delivery intoa puncture through tissue, and a second section fused to and extendingfrom the distal end of the first section. The first section may beformed from a freeze-dried hydrogel that expands when exposed tophysiological fluid within a puncture. The second section may be formedfrom a solid mass of non-freeze-dried, non-cross-linked hydrogelprecursors, the precursors remaining in an unreactive state untilexposed to an aqueous physiological, whereupon the precursors undergoin-situ cross-linking with one another to provide an improved adhesionof the sealant to the arteriotomy.

In one embodiment, the first section may consist essentially offreeze-dried hydrogel, and the second section may consist essentially ofthe non-cross-linked precursors. Alternatively, the second section mayinclude one or more reinforcement elements, e.g., a plurality offilaments or particles, mixed with, embedded in, or surrounding theprecursors. In addition or alternatively, the second section may includeone or more diluents to enhance one or more properties of the secondsection.

Optionally, the sealant may include one or more pH adjusting agents,e.g., impregnated into, coated over, or otherwise included in the firstand/or section sections. For example, when the sealant is exposed withina puncture, the agent(s) may alter the localized pH on or around thesealant, e.g., to enhance cross-linking of the precursors and/orcreation of a desired adhesive material. Alternatively, the materialsfor the precursors may be selected such that the pH and/or bufferingcapacity of interstitial body fluids and/or blood are effective to driveor facilitate cross-linking of the precursors and the pH adjustingagents may be omitted.

In accordance with another embodiment, a sealant is provided for sealinga puncture through tissue that includes an elongate first sectionincluding a proximal end, a distal end, and a cross-section sized fordelivery into a puncture through tissue, the first section consistingessentially of a freeze-dried hydrogel that expands when exposed tophysiological fluid within a puncture; and a second section fused to andextending from the distal end of the first section, the second sectionconsisting essentially of a solid mass of non-freeze-dried,non-cross-linked hydrogel precursors, the precursors remaining in anunreactive state until exposed to an aqueous physiological environment,whereupon the precursors undergo in-situ cross-linking to provide anadhesive layer to bond the first section relative to adjacent tissue.

In accordance with still another embodiment, a sealant is provided forsealing a puncture through tissue that includes an elongate bodyincluding a proximal end, a distal end, and a cross-section extendingbetween the proximal and distal ends sized for delivery into a puncturethrough tissue. The elongate body may consist essentially of a solidmass of non-freeze-dried, non-cross-linked hydrogel precursors, theprecursors remaining in an unreactive state until exposed to an aqueousphysiological environment, whereupon the precursors undergo in-situcross-linking to provide an adhesive material that bonds or adheres toadjacent tissue within the puncture. Alternatively, the elongate bodymay also include one or more reinforcement members, one or morediluents, and/or one or more pH adjusting agents.

In accordance with yet another embodiment, a sealant is provided forsealing a puncture through tissue that includes a first sectionincluding a proximal end, a distal end, and a cross-section sized fordelivery into a puncture through tissue, and a second section fused toand extending from the distal end of the first section. The firstsection may be formed from a freeze-dried hydrogel that expands whenexposed to physiological fluid within a puncture. The second section mayconsisting essentially of a solid mass of non-freeze-dried,non-cross-linked hydrogel precursors and one or more pH adjustingagents, reinforcement elements, and/or diluents mixed with theprecursors to enhance one or more mechanical properties of the secondsection.

In accordance with still another embodiment, a method is provided formaking a sealant for sealing a puncture through tissue that includesforming an elongated first section including a proximal end, a distalend, and a cross-section sized for delivery into a puncture throughtissue. The first section may be formed from a freeze-dried hydrogel orother biocompatible, bioabsorbable material that expands when exposed tophysiological fluid within a puncture. A solid mass of non-cross-linkedhydrogel precursors may be fused or otherwise attached onto the distalend, the precursors remaining in an unreactive state until exposed to anaqueous physiological environment, whereupon the precursors undergoin-situ cross-linking with one another to provide an improved adhesionto the arteriotomy. For example, the solid mass may be formed as asubstantially uniform solid plug or may be formed as a sintered mass ofpowder.

In accordance with yet another embodiment, a method is provided formaking a sealant for sealing a puncture through tissue that includesforming a sheet of the freeze-dried hydrogel that expands when exposedto physiological fluid within a puncture; rolling the sheet into atubular roll including a lumen extending between the proximal and distalends; and loading the tubular roll into a tubular member such the distalend of the tubular roll is offset inwardly from a first end of thetubular member. A plurality of non-cross-linked hydrogel precursors maybe mixed and melted, optionally with one or more diluents, theprecursors remaining in an unreactive state until exposed to an aqueousphysiological, whereupon the precursors undergo in-situ cross-linking.The melted precursors may be applied to the distal end of the tubularroll within the tubular member, and allowed to solidify to create thesolid mass fused to the distal end of the tubular roll.

In accordance with another embodiment, an apparatus is provided forsealing a puncture through tissue that includes a tubular memberincluding a proximal end, a distal end sized for insertion into apuncture, a lumen extending between the proximal and distal ends, and adistal opening in communication with the lumen, a sealant within thelumen, and an advancer member within the lumen for deploying the sealantfrom the lumen out the distal opening, e.g., when the tubular member isretracted from a puncture relative to the advancer member. The sealantmay include a first section including proximal and distal ends, and asecond section fused to and extending from the distal end. The sealantmay be disposed within the lumen such that the second section isdisposed closer to the distal opening than the first section. In anexemplary embodiment, the first section may be formed from afreeze-dried hydrogel that expands when exposed to physiological fluidwithin a puncture, and/or the second section may be formed fromnon-cross-linked hydrogel precursors, the precursors remaining in anunreactive state until exposed to an aqueous physiological environment,whereupon the precursors undergo in-situ cross-linking with one anotherto provide improved adhesion to the arteriotomy.

In accordance with still another embodiment, a method is provided forsealing a puncture through tissue that includes providing sealantincluding a first section including proximal and distal ends, and asecond section fused to and extending from the distal end. In anexemplary embodiment, the first section may be formed from afreeze-dried hydrogel, and/or the second section may be formed fromnon-cross-linked hydrogel precursors in an unreactive state. The sealantmay be introduced into a puncture through tissue with the second sectionentering the puncture before the first section. The sealant may beexposed to fluid within the puncture, whereupon the precursors of thesecond section undergo in-situ cross-linking with one another to provideimproved adhesion to the arteriotomy, and the freeze-dried hydrogel ofthe first section expands to fill space within the puncture to providehemostasis.

In accordance with another embodiment, a sealant is provided thatincludes a first section and a second section that includesnon-cross-linked hydrogel precursors in an unreactive state, e.g.,PEG-ester precursors and PEG-amine precursors. In an exemplaryembodiment, an excess of ester in the ratio of PEG-ester/PEG-amine maybe provided, i.e., such that the equivalent ratio of active group sitesof PEG-ester to PEG-amine is about 1:1 or greater. For a fullycross-linked hydrogel network the ideal equivalent ratio of active groupsites of PEG-ester and PEG-amine should be 1:1, i.e., equal number ofactive ester and amine sites that react with each other.

However, PEG-ester as a raw material (N-Hydroxysuccinimide or similarester) is less stable and may get deactivated (e.g., by hydrolysis)faster than the PEG-amine. In other words, the ratio of the active groupsites of PEG-ester to PEG-amine may effectively be less than 1:1, whichmay result in slower activation times for cross-linking and/or reducedintegrity of the final cross-linked hydrogel.

In addition, if the PEG-amine used in the second section is the H—X saltform of the PEG-amine (—NH₂—HX, where H—X may be HCl, HBr, HF or othermineral or organic acid), when the PEG-amine salt contacts physiologicalfluids, it rapidly establishes equilibrium with the fluid such that—NH₃—X

—NH₂+H—X. When the PEG-amine group (in the salt for reacts with thePEG-ester group, the above equilibrium is shifted to the right. If H—Xis a strong acid (as in the case of hydrochloric acid), it completelydisassociates into H⁺+X⁻ ions, which results in a localized decrease ofthe pH, lower than the typical pH of physiological fluid of 7.4. Thislocalized acidic environment may result in the reduction of the reactionrate and subsequently in reduced formation of in-situ crosslinks. Anexcess of PEG-ester in the ratio of PEG-ester/PEG-amine may compensatefor these issues and/or otherwise provide faster activation upon contactwith physiological fluids.

In another embodiment, the PEG-ester and PEG-amine precursors of thesecond section may be partially cross-linked, i.e., some of theprecursors may be cross-linked while the rest of the precursors mayremain in an unreactive state, e.g., such that the unreactive precursorsundergo in-situ cross-linking with one another upon contact withphysiological fluids.

In accordance with another embodiment, a sealant is provided for sealinga puncture through tissue that includes an elongate first sectionincluding proximal and distal ends; and a second section extending fromthe distal end, the second section comprising PEG-precursors comprisingPEG-ester and PEG-amine precursors with an equivalent ratio of activegroup sites of PEG-ester to PEG-amine greater than one-to-one (1:1), atleast some of the precursors remain in an unreactive state until exposedto an aqueous physiological environment, whereupon the precursorsundergo in-situ cross-linking with one another to provide adhesion totissue adjacent the puncture. In addition or alternatively, thePEG-amine precursors of the second section comprise both the free amineform of PEG-amine precursors and the salt form of PEG-amine precursors.For example, the free amine form of PEG-amine precursors may be at leastpartially cross-linked with the PEG-ester precursors, and the salt formof PEG-amine precursors may remain in the unreactive state until exposedto an aqueous physiological environment, whereupon the salt form ofPEG-amine precursors undergo in-situ cross-linking with the PEG-esterprecursors to provide adhesion to tissue adjacent the puncture.

In accordance with yet another embodiment, a sealant is provided forsealing a puncture through tissue that includes an elongate firstsection including proximal and distal ends; and a second sectionextending from the distal end of the first section, the second sectioncomprising PEG-precursors comprising PEG-ester and PEG-amine precursors,the PEG-amine precursors including both a free amine form of PEG-amineprecursors that are at least partially cross-linked with the PEG-esterprecursors and a salt form of PEG-amine precursors that remain in anunreactive state until exposed to an aqueous physiological environment,whereupon the salt form of PEG-amine precursors undergo in-situcross-linking with the PEG-ester precursors to provide adhesion totissue adjacent the puncture.

In accordance with still another embodiment, a sealant is provided forsealing a puncture through tissue that includes an elongate firstsection including a proximal end, a distal end, and a cross-sectionsized for delivery into a puncture through tissue, the first sectionconsisting essentially of a freeze-dried hydrogel that expands whenexposed to physiological fluid within a puncture; and a second sectionfused to and extending from the distal end of the first section, thesecond section formed from a solid mass of PEG-precursors consistingessentially of PEG-ester and PEG-amine precursors with an equivalentratio of PEG-ester to PEG-amine active group sites greater thanone-to-one (1:1), at least some of the precursors remaining in anunreactive state until exposed to an aqueous physiological environment,whereupon the precursors undergo in-situ cross-linking with one anotherto provide adhesion to tissue adjacent the puncture.

In accordance with another embodiment, a method is provided for making asealant for sealing a puncture through tissue that includes forming anelongate first section including a proximal end, a distal end, and across-section sized for delivery into a puncture through tissue; meltingPEG-amine and PEG-ester powders into a liquid mixture comprisingnon-cross-linked PEG precursors, wherein an equivalent ratio ofPEG-ester to PEG-amine active group sites is greater than one-to-one(1:1); and fusing a solid mass of the mixed PEG precursors onto thedistal end, at least some of the PEG precursors remaining in anunreactive state until exposed to an aqueous physiological, whereuponthe precursors undergo in-situ cross-linking with one another to providean adhesive layer bonded to the first section.

In accordance with yet another embodiment, an apparatus is provided forsealing a puncture extending through tissue that includes a tubularmember comprising a proximal end, a distal end sized for insertion intoa puncture, a lumen extending between the proximal and distal ends, anda distal opening in communication with the lumen; and a sealantcomprising an elongate first section including proximal and distal ends,and a second section fused to and extending from the distal end, thesealant disposed within the lumen such that the second section isdisposed closer to the distal opening than the first section, the secondsection comprising PEG-precursors comprising PEG-ester and PEG-amineprecursors wherein the equivalent ratio of PEG-ester to PEG-amine activegroup sites is greater than one-to-one (1:1), at least some of theprecursors remaining in an unreactive state until exposed to an aqueousphysiological environment, whereupon the precursors undergo in-situcross-linking with one another to provide adhesion to tissue adjacentthe puncture.

In accordance with still another embodiment, a method is provided forsealing a puncture extending through tissue of a patient that includesproviding sealant comprising a first section including proximal anddistal ends, and a second section extending from the distal end, thesecond section comprising PEG-precursors comprising PEG-ester andPEG-amine precursors in an equivalent ratio of PEG-ester to PEG-amineactive group sites greater than one-to-one (1:1), at least some of thePEG precursors in an unreactive state; introducing the sealant into apuncture through tissue with the second section entering the puncturebefore the first section; and exposing the sealant to fluid within thepuncture, whereupon the at least some of the PEG precursors of thesecond section undergo in-situ cross-linking with one another to provideadhesion to tissue adjacent the puncture.

Other aspects and features of the present invention will become apparentfrom consideration of the following description taken in conjunctionwith the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

It will be appreciated that the exemplary apparatus shown in thedrawings are not necessarily drawn to scale, with emphasis instead beingplaced on illustrating the various aspects and features of theillustrated embodiments.

FIG. 1 is a perspective view of an exemplary embodiment of a sealantmember including a main section, e.g., formed from freeze-driedhydrogel, and a distal tip section, e.g., formed from non-cross-linkedprecursors.

FIG. 1A is a cross-sectional view of a transfer tube and mandrel,showing a method for making the sealant member of FIG. 1.

FIG. 2A is a side view of an exemplary embodiment of an apparatus fordelivering a sealant into a puncture through tissue, including apositioning member, and a cartridge movable over the positioning memberthat includes the sealant.

FIG. 2B is an exploded perspective view of the apparatus of FIG. 2A.

FIG. 2C is a partial cross-sectional side view of the apparatus of FIGS.2A and 2B.

FIGS. 3A-3G are cross-sections of a patient's body showing a method forsealing a puncture using the apparatus of FIGS. 2A-2C.

FIGS. 4A and 4B are side views of a first alternative embodiment of asealant being compressed against an arteriotomy, e.g., using theapparatus and methods of FIGS. 2A-3G.

FIGS. 5A and 5B are side views of a second alternative embodiment of asealant being compressed against an arteriotomy, e.g., using theapparatus and methods of FIGS. 2A-3G.

FIGS. 6A-6C are side views of a third alternative embodiment of asealant being compressed against an arteriotomy, e.g., using theapparatus and methods of FIGS. 2A-3G.

FIGS. 7A and 7B are side views of a fourth alternative embodiment of asealant being compressed against an arteriotomy, e.g., using theapparatus and methods of FIGS. 2A-3G.

FIGS. 8A-8C are side views of a fifth alternative embodiment of asealant being compressed against an arteriotomy, e.g., using theapparatus and methods of FIGS. 2A-3G.

FIG. 9 includes side views of additional alternative embodiments ofsealants including a freeze-dried hydrogel section and one or morenon-cross-linked precursor sections.

FIGS. 10A-10C are perspective views of another embodiment of a sealant,showing a method for creating an adhesive coating on a base section ofmaterial to provide the sealant.

FIG. 10D is a cross-sectional view of a patient's body showing a methodfor sealing a puncture using the sealant of FIGS. 10A-1 C.

FIG. 11A is a perspective view of an exemplary embodiment of a patch forsealing a puncture in tissue.

FIG. 11B is a cross-sectional view of the patch of FIG. 11A taken alongline 11B-11B.

FIGS. 12A and 12B are side views of alternative embodiments ofnon-cross-linked precursor sections that may be provided on a sealant,such as that shown in FIG. 1.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS

Turning to the drawings, FIG. 1 shows an exemplary embodiment of asealant 2 for sealing a puncture extending through tissue (not shown).Generally, the sealant 2 includes a first, proximal, or main section 4including proximal and distal ends 4 a, 4 b, and a second, distal, ortip section 6 formed from a plurality of non-freeze-dried and/ornon-cross-linked precursors, e.g., formed as a solid mass or solid plug,fused or otherwise attached to and extending distally from the distalend 4 b of the first section 4. As described further below, thenon-cross-linked precursors may remain in an unreactive state, e.g.,before or until exposure to an aqueous physiological environment, e.g.,when deployed or otherwise exposed within a puncture extending throughtissue.

For example, this configuration of sealant 2 may combine cross-linkingof the second section 6 to create an adhesive material in-situ withswell characteristics of a freeze-dried hydrogel or other expandablematerial of the first section 4. By improving the adherencecharacteristics of the expandable hydrogel, the sealant 2 may provideenhanced extra-vascular closure, e.g., by providing expansion of thefirst section 4 in combination with improved adhesion of the sealant 2to tissue surrounding an arteriotomy or other adjacent tissue structure,e.g., entirely extra-vascularly or extending partially into thearteriotomy and/or vessel, by virtue of the in-situ polymercross-linking that occurs at the second section 6 of the sealant 2.

As shown, the first section 4 may be formed generally into an elongatecylindrical shape, e.g., including proximal and distal ends 4 a, 4 b,and an outer surface 4 c extending therebetween. Optionally, as shown inphantom, the sealant 2 may include a lumen 5 extending between theproximal and distal ends 4 a, 4 b of the first section 4 and through thesecond section 6, e.g., to facilitate delivery of the sealant 2. Forexample, the lumen 5 may be dimensioned to accommodate receiving aballoon catheter or other positioning member 14 (not shown, see, e.g.,FIGS. 2A-2C and associated description below) therethrough, e.g., suchthat the sealant 2 may slide relative to or pass over the positioningmember 14 and/or the positioning member 14 may be directed axiallyrelative to the sealant 2, as described further below. Alternatively,the sealant 2 may be a substantially continuous rod of material, e.g.,such that the sealant 2 may be delivered into a puncture using acartridge or shuttle without a positioning member (not shown).

In an exemplary embodiment, the first section 4 may be formed from asheet of freeze-dried hydrogel rolled into a tabular shape, e.g., asdisclosed in U.S. Publication No. 2007/0231336, the entire disclosure ofwhich is expressly incorporated by reference herein. It will beappreciated that the first section 4 may have other tubular or solid rodcross-sections or shapes, as desired, such as cylindrical, elliptical,triangular, square, conical, disk, polygonic shapes, and the like (notshown).

In exemplary embodiments, the sealant 2 may have an overall lengthbetween about three and twenty millimeters (3-20 mm), e.g., betweenabout five and ten millimeters (5-10mm) or between about fifteen andtwenty millimeters (15-20 mm), and an outer diameter or othercross-section between about one and eight millimeters (1-8 mm), e.g.,between about one and three millimeters (1-3 mm), between about 1.5 andtwo millimeters (1.5-2.0 mm), e.g., about 0.069 inch (1.75 mm). In theembodiment shown in FIG. 1, the first section 4 is substantially longerthan the second section 6, although it will be appreciated that,alternatively, the sections 4, 6 may have similar lengths, or the secondsection 6 may be longer than the first section 4. In a furtheralternative embodiment, the first section 4 may be omitted, and thesecond section 6 may provide the entire length of the sealant 2 (notshown), e.g., having a length between about three and twenty millimeters(3-20 mm).

For example, the first section 4 may have a length between about zero(if the sealant 2 is formed entirely from the second section 6) andtwenty millimeters (0-20 mm), e.g., between about five and twentymillimeters (5-20 mm), e.g., about fifteen millimeters (15 mm). Thesecond section 6 may have an outer diameter similar to the first section4, but may have a length that is substantially shorter, e.g., betweenabout zero (if the sealant 2 is formed entirely from the first section4) and eight millimeters (0-8 mm), e.g., between about half and fivemillimeters (0.5-5.0 mm), e.g., about 1.5 millimeters.

The first section 4 may be formed from a biocompatible and/orbioabsorbable material, for example, a porous and/or bioabsorbablehydrogel, that may have desired expansion characteristics when hydrated.In one embodiment, the first section 4 may be formed entirely from afreeze-dried and cross-linked hydrogel, e.g., polyethylene glycol(”PEG”), or other synthetic material, as disclosed in U.S. PublicationNo. 2007/0231336, incorporated by reference above, although optionallyincluding a transition zone (not shown) where the material of the secondsection 6 has penetrated partially into the distal end 4 b of the firstsection 4, e.g., during fusion, as described further below.

For example, the PEG polymer for the hydrogel sealant may include twocomponents of Polyethylene Glycol Hydrogel, e.g., PEG-amine: 8A20K-NH2and PEG-ester: 4A10K-CM-HBA-NHS, e.g., as disclosed in the referencesincorporated by reference above. In an exemplary embodiment, the molarratio of PEG-amine/PEG-ester may be between 1:9 (10% PEG-amine:90%PEG-ester) and 9:1 (90% PEG-amine:10% PEG-ester), for example, about a1:1 ratio. In another embodiment, the equivalent ratio of active groupsites of PEG-amine to PEG-ester may be about a 1:1 ratio.

In alternative embodiments, the first section 4 may be formed from othermaterials, such as pro-thrombotic material, e.g., including one or morebiological pro-thrombotics, such as collagen, fibrin,carboxymethylcellulose, oxidized cellulose, alginates, gelatin, or otherprotein-based material, and/or synthetic materials, e.g., aspolyglycolic acids (PGA's), polylactides (PLA's), polyvinyl alcohol(PVA), and the like. The material of the first section 4 may be at leastpartially absorbed by the body over time, e.g., over a period of days,weeks, or months.

Optionally, the first section 4 (and/or second section 6) may includetherapeutic and/or pharmaceutical agents, e.g., to promote healing,prevent infection and/or other adverse medical events, and the like.Such agents may be embedded in the material and/or applied as one ormore coatings or layers. In addition, the material of the first section4 may have a substantially uniform composition or the composition may bevaried, e.g., along its length and/or within underlying layers withinthe first section 4.

In an exemplary embodiment, the first section 4 may be formed entirelyfrom freeze-dried hydrogel, e.g., initially formed as a thin sheet offreeze-dried polymer. For example, to fabricate the first section 4 froma PEG hydrogel material, PEG-amine and PEG-ester powders intended toform the hydrogel may be filled into separate vials. Phosphate andborate buffers may be mad, e.g., by dissolving the sodium borate andsodium phosphate in sterile water for injection (WFI) and adjusting thepH of each solution to meet pre-established requirements. The two PEGpowders may then be dissolved in their respective buffer solutions.These precursor solutions may be mixed together, poured into trays, andfreeze-dried. The freeze-dried material may be subjected to a series ofheat and/or humidity conditioning cycles, e.g., to complete thepolymerization reaction.

The freeze-dried and conditioned sheet of hydrogel sealant may then betrimmed according to size and mass requirements, e.g., cut to a desiredlength for the finished first section 4. For example, as shown in FIG.1A, the trimmed hydrogel may be dried, rolled, and loaded into atransfer tube 8 for subsequent attachment to the second section 6.Additional information on materials and methods for making the firstsection 4 may be found in U.S. Publication No. 2007/0231366,incorporated by reference above.

To fabricate the non-freeze-dried, non-cross-linked distal section 6 ofthe sealant 2, PEG-amine and PEG-ester powders (or other cross-linkablepolymer precursors) may be melted in a beaker, mixed, and heated at apre-determined temperature and duration. For example, the precursors maybe melted in a substantially dry air or inert gas environment, e.g., tominimize or prevent entrapment of moisture, which may otherwise causehydrolysis of the PEG-ester and/or premature cross-linking. Using avacuum generator, the melted PEG may then be applied onto the distal end4 b of the rolled freeze-dried first section 4.

For example, as described above, the first section 4 may be formed froma rolled sheet and loaded into a transfer tube 8, as shown in FIG. 1A,such that the second section 6 may be fused or otherwise attached to thefirst section 4. The transfer tube 8 may have an inner diameter or othercross-section corresponding to the desired outer diameter orcross-section for the finished sealant 2. The transfer tube 8 may beformed from any material sufficient to handle the processing parametersof the assembly process, such as polymers, metals, or compositematerials, and may optionally include desired coatings, e.g., PTFE tofacilitate insertion of the first section 4 and/or removal of thesealant 2.

The first section 4 may be loaded into the transfer tube 8 such that thedistal end 4 b of the first section 4 is offset inwardly a predetermineddistance L6 from the end of the transfer tube 8, e.g., corresponding toor greater than the desired length of the second section 6. For example,for a desired finished length of the second section 6 of about 1.5millimeters, the distal end 4 b may be offset inwardly about twomillimeters (2.0 mm) from the end of the transfer tube 8 (with anyexcess material may trimmed off later, as described below). Using thevacuum generator, the melted non-cross-linked PEG is then applied ontothe distal end 4 b of the rolled freeze-dried sealant, e.g., the vacuumdirecting the melted PEG into the transfer tube 8 and against the distalend 4 b of the first section 4 (as represented by the arrow labeled“vacuum”). Thus, the transfer tube 8 may mold the melted PEG into thedesired shape, e.g., diameter and/or length, for the second section 6.

The vacuum may cause the melted precursors to nominally abut the distalend 4 b of the first section 4, and/or may partially draw the meltedprecursors into the pores and/or other open spaces within the firstsection 4, e.g., due to capillary action and the like. In thissituation, a transition zone 7 may be created within the distal end 4 bof the first section 4 in which the melted precursors permeate thefreeze-dried hydrogel or other material of the first section 4, whichmay enhance fusing the second section 6 to the first section 4. Forexample, the melted precursors may quickly cool under ambient conditionssuch that the penetration into the distal end 4 b may be relativelyshort, e.g., resulting in a transition zone 7 of one millimeter (1 mm)or less.

The melted precursors may be dried under ambient conditions, e.g.,simply allowed to cool and solidify, or alternatively, the melted andapplied precursors may be exposed to desired conditions to accelerate orfacilitate solidification of the melted precursors. The vacuum processeffectively fuses the two sections together to provide a length ofsealant 2.

If desired, the resulting sealant 2 may then be trimmed to length, asdesired, e.g., for loading into a delivery apparatus, e.g., a cartridgeor shuttle, such as those described further below and in the referencesincorporated by reference herein. For example, any excess length of thesecond section 6 may be removed, e.g., by mechanical cutting, lasercutting, and the like, to provide the desired length for the finalsecond section 6. In addition or alternatively, the first section 4 maybe trimmed to a desired length, e.g., by cutting the proximal end 4 abefore loading the first section 4 into the transfer tube 8 (asdescribed above) and/or after fusing the second section 6 to the distalend 4 b.

In addition or alternatively, if the sealant 2 and/or first section 4includes a lumen 5, the lumen 5 may be created when the first section 4is formed, e.g., if the first section 4 is rolled from one or moresheets or layers of material or formed by molding. Alternatively, thelumen 5 may be formed by boring into or otherwise removing material froman already formed and solid first section 4, second section 6, orthrough the entire sealant 2. For example, if the first section 4 isformed from a rolled sheet, a rod or other mandrel 9 (which may befabricated similar to the transfer tube 8) may be inserted through thelumen 5 before the second section 6 is applied to the distal end 4 b,e.g., that extends from the transfer tube 8, as shown in FIG. 1A. Thus,the second section 6 may be molded and fused to distal end 4 b aroundthe mandrel 9, e.g., within the transfer tube 8. The mandrel 8 may beremoved once the melted precursors have solidified, resulting in acontinuous lumen through the second section 6 and the first section 4.Alternatively, the portion of the lumen 5 through the second section 6may be bored, drilled, or otherwise created after the second section 6is formed and fused to the first section 5.

In exemplary embodiments, the precursors for the second section 6 mayinclude one or more of the following:

a) Polyethylene glycol derivatives or polyethylene glycols with at leasttwo end groups (2 Arms) and having at least one cross-linkable endgroups. The first functional groups may chemically react with the secondfunctional groups in-situ to form covalent bonds and thereby form across-linkable gel.

b) The first functional groups or second functional groups may be chosenfrom groups that are strong electrophiles, e.g., epoxide, succinimide,N-hydroxysuccinimide, acrylate, methacrylate, maleimide, andN-hydroxysulfosuccinimide in addition to a group including amine,sulfhydryl, carboxyls, or hydroxyls.

c) The molecular weight of the polyethylene glycols may range from 5000to 40,000 Da and may include at least about 2 to 8 functional groups.

d) Examples of the polyethylene glycols derivatives that may be usedinclude but are not limited to the following formulations:

-   -   i) Branched PEG Derivatives:    -   Y-Shape PEG NHS Ester, MW 40000    -   Y-Shape PEG Maleimide, MW 40000    -   Y-Shape PEG Acetaldehyde, MW 40000    -   Y-Shape PEG Propionaldehyde, MW 40000    -   ii) Heterofunctional PEG Derivatives:    -   Hydroxyl PEG Carboxyl, MW 3500    -   Hydroxyl PEG Amine, HCl Salt, MW 3500    -   Amine PEG Carboxyl, HCl Salt, MW 3500    -   Acrylate PEG NHS Ester, MW 3500    -   Maleimide PEG Amine, TFA Salt, MW 3500    -   Maleimide PEG NHS Ester, MW 3500    -   4 Arm PEG Succinimidyl Succinate (pentaerythritol), MW 10 KDa    -   8 Arms PEG Amine, MW 10-20 KDa    -   iii) Linear Monofunctional PEG Derivatives:    -   Methoxy PEG Succinimidyl Carboxymethyl Ester, MW 10-20K    -   Methoxy PEG Maleimide, MW 10-20K,    -   Methoxy PEG Vinylsulfone, MW 10-20K    -   Methoxy PEG Thiol, MW 10-20K    -   Methoxy PEG Propionaldehyde, MW 10-20K    -   Methoxy PEG Amine, HCl Salt, MW 10-20K

In an exemplary embodiment, the second section 6 may be formed from PEGpolymer that includes two components of Polyethylene Glycol Hydrogel,e.g., PEG-amine: 8A20K-NH2 and PEG-ester: 4A10K-CM-HBA-NHS, e.g., asdisclosed in the references incorporated by reference above. In anexemplary embodiment, the equivalent ratio of PEG-amine to PEG-esteractive group sites may be between 1:9 (10% PEG-amine:90% PEG-ester) and9:1 (90% PEG-amine:10% PEG-ester), for example, about a 1:1 ratio.

In another exemplary embodiment, an excess of PEG-ester in the mixtureof the PEG-ester with the PEG-amine, e.g., with the PEG-ester/PEG-amineequivalent ratios being between about 65/35 to 55/45(PEG-ester/PEG-amine ratio), or about 60/40 (PEG-ester/PEG-amine ratio).

For example, for a fully cross-linked hydrogel network the idealequivalent ratio of active group sites of PEG-ester and PEG-amine shouldbe 1:1, i.e., equal number of active ester and amine sites that reactwith each other. However, PEG-ester as a raw material is less stable andmay get deactivated (e.g., by hydrolysis)faster than the PEG-amine. Inother words, the PEG-ester/PEG-amine equivalent ratio may effectively beless than 1:1, which may result in slower activation times forcross-linking and/or reduced integrity of the final cross-linkedhydrogel.

In addition, if the PEG-amine used in the second section is the H—X saltform of the PEG-amine (—NH₂—HX, where H—X may be HCl, HBr, HF or othermineral or organic acid), when the PEG-amine salt contacts physiologicalfluids, it rapidly establishes equilibrium with the fluid such that —NH₃

—NH₂+H—X. When the PEG-amine group (in the salt form) reacts with thePEG-ester group the above equilibrium is shifted to the right. If H—X isa strong acid (as in the case of hydrochloric acid), it completelydisassociates into H⁺+X⁻ ions, which results in a localized decrease ofthe pH, lower than the typical pH of physiological fluid of 7.4. Thislocalized acidic environment may result in a decrease of the reactionrate and subsequently in reduced formation of in-situ crosslinks. Anexcess of PEG-ester in the ratio of PEG-ester/PEG-amine may compensatefor these issues and/or otherwise provide faster activation upon contactwith physiological fluids.

In addition or alternatively, if desired, the precursors in the secondsection 6 may be partially cross-linked with one another, e.g., thesecond section 6 may be formed from PEG-ester and PEG-amine precursorsthat have partially been cross-linked. In an exemplary embodiment, thePEG-amine precursors included in the mixture with the PEG-ester mayinclude both the free amine form of the PEG-amine and the salt form ofthe PEG-amine. For example, a mixture of PEG-ester precursors with boththe free amine form as well as the salt form of PEG-amine precursors maybe melted, e.g., at a temperature of about seventy five degrees Celsius(75° C.). The free amine form of the PEG-amine may be very reactive andmay react in the presence of PEG-ester upon melting even under dryconditions. Thus, the result of this process is that a partiallycross-linked network is provided in the final second section 6, whichmay cross-link further (may be activated) upon entering the body in thepresence of physiological fluids. In exemplary embodiments, theequivalent ratios of active group sites of PEG-ester/REG-amine (saltform)/PEG-amine (free amine form) may be between about 50/45/5 and70/25/5, or 60/35/5 (PEG-ester/PEG-amine (salt form)/PEG-amine (freeamine form)).

Thus, the free amine form of PEG-amine precursors may be at leastpartially or substantially completely cross-linked (e.g., as limited bysteric hindrance) with corresponding PEG-ester precursors, while thesalt form of PEG-amine precursors (and corresponding PEG-esterprecursors) may remain in an unreactive state until exposed tophysiological fluids. The resulting second section 6 may provide apredetermined amount of ester and amine groups (less than all of thegroups in the second section 6) left to react and get activated uponcontact with physiological fluids.

Several studies were performed to evaluate the performance of variousequivalent ratios of active group sites of the PEG-ester and PEG-amineprecursors, e.g., compared to an equivalent ratio of active group sitesof PEG-ester to PEG-amine of about 1 to 1.

EXAMPLE 1

Bovine arteries were purchased from Lampire Biological Laboratories (PA,USA) and were cut into about one-by-one inch (˜2,5 cm×2.5 cm) squares. Atwo millimeter (2 mm) puncture (surgical puncture) was performed in themiddle of the bovine arteries. The artery filets were cast on top of afixture opening that is held under liquid pressure (PBS, 37° C.)simulating an arterial wound opening that is held under arterialpressure. Mixtures of melted PEG-ester (4-arm-10K-CM-HBA-NHS) andPEG-amine (8-arm-20K-PEG-NH3⁺Cl⁻) were cast into disks (6 mm diameter,0.5 mm height) under nitrogen. The casted PEG disks were put on top ofthe arterial hole. Fifty microliters (50 μL) of PBS were applied on top.After six (6) minutes, the pump was turned on at about 0.2 psi. At seven(7) minutes, the pressure was increased by 0.5 psi increments. Thepressure was held for twenty seconds (20 sec) at each increment; thepressure at which leakage occurs was recorded.

Tests were performed on pieces of the same artery on the same day andhave been performed in sequence to increase confidence (e.g., test50/50, then 60/40, then 50/50, etc.). Summarized results of the pressurethat each formulation can withstand can be seen below. Results indicatethat when an excess of PEG-ester active group sites is utilized in thePEG-ester/PEG-amine equivalent ratio mixture, the pressure that thecasted disk can withstand is higher.

Pressure (psi) Withstood Ester/Amine equivalents Ester/Amine equivalentsSample # ratio 50/50 ratio 59.5/40.5 1 8.5 7.5 2 2 6 3 1 4.5 4 5 8 5 1.53.5 6 1.5 3.5 Avg 3.25 5.5 St dev 2.95 1.80

EXAMPLE 2

Bovine arteries were purchased from Lampire Biological Laboratories (PA,USA) and were cut into about one-by-one inch 2.5 cm×2.5 cm) squares. Atwo millimeter (2 mm) puncture (surgical puncture) was performed in themiddle of the bovine arteries. The artery filets were cast on top of afixture opening that is held under liquid pressure (PBS, 37° C.)simulating an arterial wound opening that is held under arterialpressure. Mixtures of melted PEG-ester (4-arm-1.0K-CM-HBA-NHS) andPEG-amine (8-arm-20K-PEG-NH3⁺Cl⁻) were cast into disks (6 mm diameter,0.5 mm height) under nitrogen. The casted PEG disks were put on top ofthe arterial hole. Fifty microliters (50 μL) of PBS were applied on top.After six (6) minutes, the pump was turned on at about 0.2 psi. At seven(7) minutes, the pressure was increased by 0.5 psi increments. Thepressure was held for twenty seconds (20 sec) at each increment; thepressure at which leakage occurs was recorded.

Tests were performed on pieces of the same artery on the same day andhave been performed in sequence to increase confidence (e.g., test50/50, then 60/40, then 50/50, etc.). Summarized results of the pressurethat each formulation can withstand can be seen below. Results indicatethat when an excess of PEG-ester is utilized in the PEG-ester/PEG-amineratio, the pressure that the casted disk can withstand is higher.

Pressure (psi) Withstood Ester/Amine equivalents Ester/Amine equivalentsSample # ratio 50/50 ratio 59.5/40.5 1 9 12 2 0.5 2 3 1.5 2.5 4 0.5 0.55 0.5 2 Avg 2.4 3.8 St dev 3.71 4.64

EXAMPLE 3

Bovine arteries were purchased from Lampire Biological Laboratories (PA,USA) and were cut into about one-by-one inch 2.5 cm×2.5 cm) squares. Atwo millimeter (2 mm) puncture (surgical puncture) was performed in themiddle of the bovine arteries. The artery filets were cast on top of afixture opening that is held under liquid pressure (PBS, 37° C.)simulating an arterial wound opening that is held under arterialpressure. Mixtures of melted PEG-ester (4-arm-10K-CM-HBA-NHS) andPEG-amine (both free amine form8-arm-20K-PEG-NH2 and salt form 8-arm-20KPEG-NH3⁺Cl⁻) were cast into disks (6 mm diameter, 0.5 mm height) undernitrogen. The casted PEG disks were put on top of the arterial hole.Fifty microliters (50 μL) of PBS were applied on top. After six (6)minutes, the pump was turned on at about 0.2 psi. At seven (7) minutes,the pressure was increased by 0.5 psi increments. The pressure was heldfor twenty seconds (20 sec) at each increment; the pressure at whichleakage occurs was recorded.

Tests were performed on pieces of the same artery on the same day andhave been performed in sequence to increase confidence (e.g., test50/50, then 60/40, then 50/50, etc.). Summarized results of the pressurethat each formulation can withstand can be seen below. Results indicatethat when an excess of PEG-ester is utilized in the PEG-ester/PEG-amineratio, the pressure that the casted disk can withstand is higher. Inaddition when the network mixture of the PEG-ester with the PEG-aminehas partially been cross-linked, the casted disk can withstand muchhigher pressures as compared to the original 50/50 PEG-ester/PEG-aminemixture.

Pressure (psi) Ester/Amine Ester/Amine (salt)/Amine (salt)/AmineEster/Amine Ester/Amine (free form) (free form) (salt) (salt)equivalents equivalents equivalents equivalents ratio ratio Sample #ratio 50/50 ratio 59.5/40.5 50/44.9/5.1 60.8/33.4/5.8 1 0.5 0.5 7 6.5 20.5 2.5 4.5 5 3 1 2.5 4 7.5 4 3 7 1 5 5 0.5 0.5 8 6 0.5 5.5 7 1.5 3 Avg1.1 2.6 4.1 5.8 St dev 0.9 2.7 2.5 1.7

Optionally,the second section 6 of any of these embodiments may includeone or more pH adjusting agents. For example, a pH adjusting agent,e.g., sodium borate, sodium phosphate, sodium bicarbonate, and/or othersalts, such as Na₂B₄O₇.10H₂O in crystalline or powder form, may bemelted with the precursors and then applied with the precursors to thedistal end 4 b of the first section 4, as described above.Alternatively, the pH adjusting agent may be applied to the secondsection 6 after fusing the melted precursors to the first section 4,e.g., by bonding or impregnating crystals of borate her salts to theouter surface of the solid mass of non-cross-linked precursors and/or bymelting and applying a coating of melted salts to the outer surface,e.g., similar to embodiments disclosed in the references incorporated byreference elsewhere herein. In addition or alternatively, one or more pHadjusting agents may be provided on the first section 4, if desired.

In this manner, the pH adjusting agent may alter the localized pH on oraround the sealant 2, e.g., when deployed within a puncture to enhancecross-linking and/or creation of a desired adhesive material.Alternatively, the pH and/or buffering capacity of interstitial bodyfluids and/or blood may be effective to drive or facilitatecross-linking of the second section 6. For example, the precursors ofthe second section 6 may be optimized to take into account all of thesefactors and/or form a robust attachment tissue.

In addition or alternatively, diluents, such as low molecular PEG and/orglycerol, may be added to the formulation, i.e., the melted precursorsbefore application to the first section 4, e.g., to improve themechanical strength and/or integrity of the first section 6 and/or tominimize the brittleness of the second section 6.

In a further alternative, if desired, one or more reinforcement elementsmay be provided within the second section 6. For example, as shown inFIG. 12A, a bioabsorbable mesh 6 a′ may be embedded within and/orsurround the precursors 6 b′ of a second section 6.′ The mesh 6 a′ ofbioabsorbable material may have greater rigidity, elasticity, and/orother desired properties than the solidified precursors 6 b.′ Exemplarymaterials for the reinforcement elements may include any of thebioabsorbable materials described above for the first section 4.

As shown, the mesh 6 a′ may include one or more fibers or filamentshaving a helical configuration (one helical filament shown), oralternatively the mesh 6 a′ may include a braid of filaments, a rolledporous mat, and the like (not shown). In an exemplary embodiment, themesh 6 a′ may be embedded in the precursors 6 b′ of the second section6,′ e.g., by inserting the reinforcement element(s) into the end of thetransfer tube 8 (not shown, see FIG. 1A) before applying the meltedprecursors (not shown), as described above. Thus, as the appliedprecursors are drawn into the transfer tube 8 and cool (or are otherwisedried and/or solidified), the precursors 6 b′ may permeate throughand/or surround the mesh 6 a,′ thereby embedding the element(s) in thesecond section 6.′

Alternatively, as shown in FIG. 12B, reinforcing particles or fillers 6a″ may be provided in a second section 6.″ For example, similarcompositions of bioabsorbable material having greater rigidity,elasticity, and/or other desired properties than the precursors 6 b,″such as the materials described above, may be mixed into the meltedprecursor mixture, and then the reinforcing fillers 6 a″ may be appliedto the distal end 4 b of the first section 4 (not shown) along with theprecursors 6 b,″ e.g., using the vacuum process described above. Thus,the filler material 6 a″ may be distributed randomly, substantiallyuniformly, or in a desired pattern throughout the second section 6,″thereby enhancing the rigidity, reducing the brittleness, and/oroherwise modifying the properties of the precursors 6 b″ of the secondsection 6″ in a desired manner.

Once the sealant 2 is formed and/or trimmed, as described above, thesealant 2 may be loaded onto a delivery apparatus for use in sealing apuncture, e.g., using the methods described below.

Turning to FIGS. 2A-2C, an exemplary embodiment of an apparatus 10 isshown for sealing a puncture through tissue, e.g., using the sealant 2(or any of the other embodiments described elsewhere herein). Generally,the apparatus 10 includes a positioning member 14 and a cartridge orshuttle 16 carried on the positioning member 14 for delivering a sealant2 therein into a puncture (not shown). Optionally, the apparatus 10 maybe part of a system, e.g., which may also include a delivery, access,procedure, introducer, or other sheath 80 (not shown, see, e.g., FIGS.3A-3F). Optionally, the apparatus 10 and/or system may include one ormore other components, e.g., a needle, guidewire, and/or otherinstrument for creating a puncture, a source of inflation media, and/ora source of additional sealing compound (not shown), for example, toprovide a kit for a medical procedure.

As shown in FIGS. 2A-2C, the cartridge 16 includes an elongate tubularmember 20 carrying the sealant 2 therein, an advancer tube or member 30adjacent the sealant 2 within the tubular member 20, and a handle or hub23 coupled to the tubular member 20. Generally, as best seen in FIG. 2C,the tubular member 20 includes a proximal end 22 coupled to the hub 23,a distal end 24 sized for introduction into an introducer sheath and/orpuncture (not shown), and a lumen 26 extending between proximal anddistal ends 22, 24 of the tubular member 20. The tubular member 20 maybe substantially rigid, semi-rigid, or flexible, e.g., such that thetubular member 20 may be advanced through an introducer sheath orotherwise into a puncture through tissue. Optionally, the hub 23 mayinclude one or more detents or other features (not shown) for releasablycoupling the cartridge 16 to the positioning member 14, e.g., asdescribed in the references incorporated by reference herein.

With additional reference to FIGS. 2C, 3E, and 3F, the advancer member30 may be an elongate tubular body sized to be slidably received withinthe lumen 26 of the tubular member 20, although the advancer member 30may abut or otherwise interact with the hub 23 of the cartridge 16,e.g., such that the advancer member 30 is advanced distally when thecartridge 16 is advanced. A distal end 34 of the advancer member 30 mayterminate in a substantially blunt distal tip proximal to the tubularmember distal end 24, as best seen in FIG. 2C, e.g., by simply cuttingthe end of the advancer member 30, which may facilitate contactingand/or otherwise maintaining the sealant 2 within a puncture, e.g., whenthe tubular member 20 is retracted during use, as described furtherbelow.

The advancer member 30 may be substantially rigid, semi-rigid, and/orsubstantially flexible, e.g., having sufficient column strength to allowproximal movement of the tubular member 20 relative to the sealant 2without buckling the advancer member 30 and/or to allow the distal end34 of the advancer member 30 to be advanced to compress the sealant 2within a puncture, e.g., by pushing from the proximal end 32, asdescribed further below. As best seen in FIG. 2C, the advancer member 30may also include a lumen 36 extending between the proximal and distalends 32, 34, e.g., to accommodate the positioning member 14, a flowablesealing compound, and/or fluid (not shown).

Optionally, the advancer member 30 may include one or more elements (notshown) on the proximal end 32, e.g., for interacting with one or morecooperating elements (also not shown) on the positioning member 14,e.g., to limit movement of the advancer member 30 relative to thepositioning member 14, e.g., as described in the references incorporatedby reference herein.

As shown in phantom in FIG. 2C, the sealant 2 (which, alternatively, maybe any of the embodiments herein, e.g., sealant 102-502) may be disposedwithin the lumen 26 of the tubular member 20 proximate to the distal end24, e.g., immediately adjacent the distal tip 25. The lumen 26 may besized such that the tubular member 20 and sealant 2 are slidablerelative to one another, e.g., to allow the tubular member 20 to beretracted proximally relative to the sealant 2 and/or advancer member30, as described further below.

With continued reference to FIGS. 2A-2C, the positioning member 14generally includes an elongate member 40 including a proximal end 42(not shown, see, e.g., FIG. 2B), a distal end 44, and an occlusion orpositioning element 46 on the distal end 44. The positioning element 46may be an expandable member, such as a balloon, a wire mesh structure,an expandable frame, and the like, e.g., as disclosed in the referencesincorporated by reference herein. The positioning element 46 may beselectively expandable, e.g., using a source of inflation media, such assyringe 148, a pull wire, and/or other actuator (not shown), operablefrom the proximal end 42 of the positioning member 14.

For example, as shown, the positioning element may be a balloon 46, andthe positioning member 14 may include a tubular body 40 including alumen (not shown) extending between the proximal and distal ends 42, 44and communicating with an interior of the balloon 46. In thisembodiment, the positioning member 14 may include a source of inflationmedia, such as syringe 148, that may be coupled to a housing 48 on theproximal end 42 of the positioning member 14. Optionally, thepositioning member 14 may include an internal pull wire (not shown) thatcauses the balloon 46 to shorten during expansion and extend duringcollapse. Exemplary embodiments of positioning members 14 includingballoons that may be used are disclosed in U.S. Publication Nos.2004/0249342, 2004/0267308, 2006/0253072, and 2008/0009794. The entiredisclosures of these references are expressly incorporated by referenceherein.

Alternatively, the positioning element may be biased to an enlargedcondition, but may be compressed to a contracted condition, e.g., by anoverlying sleeve or other constraint (not shown). The constraint may beremoved to expose the positioning element, allowing the expandableelement to automatically expand to the enlarged condition. Additionalinformation on expandable structures that may be provided on thepositioning member 14 may be found in U.S. Pat. Nos. 6,238,412,6,635,068, and 6,890,343, and in co-pending application Ser. No.10/975,205, filed Oct. 27, 2004. The entire disclosures of thesereferences are expressly incorporated herein by reference.

With additional reference to FIGS. 3A-3G, the apparatus 10 may be usedto position and deliver the sealant 2 within a puncture, e.g.,extra-vascularly just above or otherwise adjacent to an arteriotomy in ablood vessel or other body lumen communicating with a puncture, asdescribed further elsewhere herein. In one embodiment, as shown in FIGS.2A and 3A, the cartridge 16 (along with the advancer member 30 andsealant 2 within the tubular member 20) may be initially provided on theproximal end 42 of the positioning member 14. For example, the housing48 on the positioning member 14 and the hub 23 on the cartridge 16 maybe initially connected to one another, e.g., using one or morereleasable detents (not shown). Alternatively, the cartridge 16 may beinitially provided such that the distal 24 of the tubular member 20 isdisposed adjacent the balloon 46, e.g., as disclosed in U.S. Pat. No.7,335,220 and U.S. Publication No. 2008/0082122, incorporated byreference elsewhere herein.

As shown in FIG. 3C, the cartridge 16 may be slidable distally along thepositioning member 14, e.g., by disconnecting the hub 23 from thehousing 48, and then advancing the cartridge 16, e.g., until the distalend 24 of the tubular member 20 is disposed adjacent the positioningelement 46. For example, detents on the hub 23 and housing 48 may simplyseparate from one another when the hub 23 is advanced away from thehousing 48 with sufficient force. Alternatively, one of the hub 23 andhousing 48 may include an actuator or lock that may be activated (notshown) to separate the detents and/or otherwise allow the cartridge 16to be advanced relative to the positioning member 14.

Optionally, the cartridge 16 and/or positioning member 14 may includecooperating features that limit distal movement of the cartridge 16relative to the positioning member 14. For example, the hub 23 of thecartridge 16 may include a pocket and the positioning member 14 mayinclude a detent or other feature (both not shown) that may be receivedwithin the pocket when the cartridge 16 is advanced to a distalposition. In addition or alternatively, the positioning member 14 and/oradvancer member 30 may include one or more elements that engage when thecartridge 16 reaches a predetermined location then advanced along thepositioning member 14, e.g., to limit subsequent proximal movement ofthe advancer member 30 relative to the positioning member 14 when thetubular member 20 is subsequently retracted, similar to embodimentsdisclosed in the references incorporated by reference herein.

In addition or alternately, one or more markers may be provided on theapparatus 10, e.g., to identify when components are located at one ormore desired positions or otherwise to facilitate use of the apparatus10. For example, the positioning member 14 may include one or moremarkers at predetermined locations on the elongate member 40. Suchmarkers may provide visual confirmation when the cartridge 16 has beenadvanced to a desired distal position, e.g., when the marker(s emergefrom the hub 23 as the cartridge 16 is advanced over the positioningmember 14. In addition or alternatively, as shown in FIG. 3E and 3F, theadvancer member 30 may include one or more markers 33 thereon, which maybe visible when the cartridge 16 is advanced to a distal position andthen the tubular member 20 is retracted to expose the sealant 2. Thesemarkers 33 may also provide visual guides to inform the user when theadvancer member 30 is manipulated, e.g., advanced into a puncture tocompress the sealant 2 therein, as described further below.

The apparatus 10 may be assembled using conventional manufacturingmethods and/or using methods disclosed in the references incorporated byreference herein. Although an exemplary process is described below asbeing performed in an exemplary order, it will be appreciated that theactual order of the assembly steps may be changed, as desired.

For example, the positioning member 14 may be formed by providing alength of tubing for the tabular body 40 and attaching a balloon 46 tothe distal end 44. To make the balloon, a section of tubing, e.g., LLDPEor other elastic material, may be cut to a predetermined length that isnecked down to a smaller diameter, e.g., using a hot die or hot airnecker. The tubing may then be placed into a balloon blower, which mayuse a split aluminum or other mold (not shown) to form the balloon 46,e.g., at a desired temperature and blow pressure. The resulting balloonsubassembly may then be trimmed as desired and attached to the distalend 44 of the tubular body 40, which may also be necked down tofacilitate attachment of the balloon 46, e.g., by an interference fit,bonding with adhesive, fusing, and the like.

The components of the cartridge 16, the tubular body 20, advancer tube30, and hub 23 may be formed using conventional methods, e.g.,extruding, molding, and the like. For example, the hub 23 may be formedfrom a plurality of molded shells that may be attached together and towhich the proximal end 22 of the tubular body 20 may be attached.

In the exemplary embodiment shown, the cartridge 16 includes a singletubular body 20 attached to the hub 23. In an alternative embodiment,the cartridge 16 may include inner and outer cartridge assemblies,including inner and outer tubular bodies (not shown) attached to the hub23, e.g., similar to embodiments disclosed in the referencesincorporated by reference herein. For example, an inner cartridgesubassembly may include tubing bonded to a molded hub, and an outercartridge subassembly may include tubing bonded to a molded slider. Theinner and outer cartridges may then be captured within halves of ashuttle shell providing the hub 23.

The advancer member 30 may include a section of tubing with athermoformed tapered tip. Once the tubular body 20 (or bodies) assembledto the hub 23, the advancer member 30 may be inserted into the lumen 26of the tubular body 20 (e.g., into the inner cartridge tubing if innerand outer cartridge tubular bodies are provided).

To provide the hub 48 of the positioning member 14, a hub barrel 48 a,stopcock 48 b, and extension line 48 c may be assembled, as shown inFIG. 2B, similar to embodiments disclosed in the references incorporatedby reference herein. One end of the extension line 48 c may be bonded orotherwise attached to the stopcock 48 b, and the other end of theextension line 48 c may be bonded or otherwise attached into the sideport of the hub barrel 48 a.

To complete the positioning member 14, locking features (not shown) maybe bonded onto the tubular body 40, e.g., spaced a predetermineddistance from the proximal end 42. The proximal leg of the balloon 46may be bonded to the distal end 44 of the tubular body 40. The cartridge16, hub barrel 48 and a core wire with tension plunger (not shown) areall then assembled with the tubular body 40, e.g., similar toembodiments in the references incorporated by reference herein. The corewire may then be bonded into the distal leg of the balloon 46. The hubbarrel 48 a is bonded to the proximal end 42 of the tubular body 40 andcaptured within the halves of the handle shell to provide the hub 48, asshown in FIG. 2.

Finally, the sealant 2 is loaded onto the assembled apparatus 10. Forexample, the rolled sealant 2 may be coaxially mounted over the tubularbody 40 from the distal end 44 and positioned inside the tubular member20 of the cartridge 16, e.g., adjacent the distal end 24 and theadvancer member 30 therein. For example, the sealant 2 stored within atransfer tube 8 (not shown, see FIG. 1A) may be aligned with the balloon46 and distal end 44 of the tubular body 40 such that the proximal end 4a of the first section 4 is oriented towards the proximal end 42 of thetubular body 40. The sealant 2 may then be transferred from the transfertube 8 over the tubular body 40 into the cartridge 20 such that thedistal section 6 is located closest to the distal end 24 within thetubular member 20.

Optionally, a thin silicone coating may be applied to the tubular body40, the tubular member 20, and the balloon 46. A protective sheath (notshown) may then be placed over the balloon 46 and at least partiallyover the tubular body 40.

The apparatus 10 and syringe 148 may then be placed with appropriatepackaging, e.g., into respective cavities within a thermoformedclamshell tray (not shown), and the clamshell tray snaps may be closed.The closed tray may be inserted into a foil pouch or other packaging asdesired. Additional processing, such as product labeling, sterilization,and the like, may be completed before the apparatus 10 is provided to auser.

Turning to FIGS. 3A-3G, an exemplary method is shown for sealing apuncture 90, e.g., using the apparatus 10 to deliver a sealant 2 (whichagain may be any of the exemplary embodiments herein), e.g., to achievehemostasis within the puncture 90. Generally, the puncture 90 extendsfrom a patient's skin 92 through intervening tissue, e.g., to a bodylumen 94. In an exemplary embodiment, the puncture 90 may be apercutaneous puncture communicating with a blood vessel 94, such as afemoral artery, carotid artery, and the like.

In an exemplary method, the puncture 90 may be created using knownprocedures, e.g., using a needle, guidewire, one or more dilators, andthe like (not shown). An introducer sheath 80 may be advanced throughthe puncture 90 into the vessel 94, e.g., over a guidewire (not shown)placed through the puncture 90 into the vessel 94. The introducer sheath80 may provide access into the vessel 92 for one or more instruments(not shown), e.g., to allow one or more diagnostic and/or interventionalprocedures to be performed via the vessel 94. Upon completing theprocedure(s) via the vessel 94, any such instrument(s) may be removedfrom the puncture 90, leaving the introducer sheath 80 extending throughthe puncture 90 into the vessel 94.

With reference to FIG. 3A, the positioning member 14 may be introducedinto and/or through the lumen of the introducer sheath 80, e.g., withthe expandable positioning element 46 in a collapsed condition. Thecartridge 16, along with the sealant 2 and advancer member 30, may beprovided initially on the proximal end 42 of the positioning member 40,e.g., as shown in FIGS. 2A and 3A. Thus, the distal end 24 of thetubular member 20 may initially be located outside the puncture 90 whenthe positioning member 40 is advanced into the puncture 90.

Still referring to FIG. 3A, the distal end 44 of the positioning member14 may be inserted through the puncture 90 (via the introducer sheath80) and into the vessel 94. Once the positioning element 46 is disposedwithin the vessel 94, i.e., beyond a distal end 84 of the introducersheath 80, the positioning element 46 may be expanded to an enlargedcondition, as shown.

After expanding the positioning element 46, the positioning member 40may be at least partially withdrawn until the positioning element 46contacts the wall of the vessel 94, e.g., to substantially seal thevessel 94 from the puncture 90. In an exemplary method, shown in FIGS.3A and 3B, this may involve a two-step process (although it may becompleted in a single substantially continuous action). First, with thepositioning element 46 expanded within the vessel 94, the positioningmember 14 may be withdrawn until the positioning element 46 contacts thedistal end 84 of the introducer sheath 80, which may provide a firsttactile feedback to the user (i.e., that the positioning element 46 hascontacted the introducer sheath 80, e.g., based upon the increasedweight and/or resistance to proximal movement). The positioning member14 may be withdrawn further until the positioning element 46 contactsthe wall of the vessel 94 and resists further withdrawal, therebyproviding a second tactile feedback. The introducer sheath 80 may bepulled proximally by the positioning element 46 as the positioningmember 14 is withdrawn, e.g., until the distal end 84 of the introducersheath 80 is withdrawn from the vessel 94 into the puncture 90, as shownin FIG. 3B.

Proximal tension may be applied and/or maintained on the positioningmember 14 to hold the positioning element 46 against the wall of thevessel 94, e.g., to seal the puncture 90 from the vessel 94 and/orprevent further removal of the positioning member 14. The proximaltension may be maintained manually or using a tensioner device (notshown) to provide temporary hemostasis, e.g., during the subsequentsteps. Exemplary tension devices are disclosed in U.S. Publication No.2004/0267308, incorporated by reference elsewhere herein.

Turning to FIG. 3C, the cartridge 16 (carrying the sealant 2) may thenbe advanced distally over the positioning member 14 into the puncture90. As shown, the distal end 24 of the tubular member 20 may enter theintroducer sheath 80 and be advanced towards the positioning element 46.The cartridge 16 may be advanced until a component of the cartridge 16encounters a stop on the positioning member 14, thereby preventingfurther advancement of the cartridge 16 and/or spacing the sealant 2 apredetermined distance from the positioning element 46. Alternatively,the cartridge 16 may be advanced into the introducer sheath 80 until thedistal end 24 contacts the expanded positioning element 46, which mayprovide tactile feedback that the cartridge 16 has been advancedsufficiently, or the sealant 2 is otherwise positioned within thepuncture 90.

Thereafter, as shown in FIG. 3D, the tubular member 20 of the cartridge16 and introducer sheath 80 may be retracted, e.g., by pullingproximally on a hub 83 of the introducer sheath 80, to withdrawn theintroducer sheath 80 and tubular member 20 from the puncture 90 andexpose the sealant within the puncture 90 beyond the introducer sheathdistal end 84. Optionally, a sleeve or locking device (not shown) may beprovided on the cartridge 16 that may couple the introducer sheath 80 tothe tubular member, similar to embodiments disclosed in Publication No.2009/0088793, the entire disclosure of which is expressly incorporatedby reference herein. Thus, in this alternative, if the user pullsproximally on the hub 23 or tubular member 20 rather than the hub 83 ofthe introducer sheath 80, the introducer sheath 80 and tubular member 20may still be withdrawn together from the puncture 90.

As the tubular member 20 is retracted, the advancer member 30 mayprevent substantial proximal movement of the sealant 2, thereby exposingthe sealant 2 within the puncture 90, as shown in FIGS. 3D and 3E. Forexample, as described above, as the cartridge 16 is advanced, one ormore features (not shown) on the proximal end 32 of the advancer member30 may pass over a reduced region or other feature (also not shown) onthe positioning member 14, thereby preventing subsequent proximalwithdrawal of the advancer member 30 relative to the positioning member14. Thus, when the cartridge 16 is then retracted, the features mayprevent substantial proximal movement of the advancer member 30, and thesealant 2 adjacent the distal end 34 of the advancer member 30.

When the sealant 2 is exposed within the puncture 90, the sealant 2 maybe exposed to blood and/or other body fluids within the puncture 90.This exposure may cause the sealant 2 to absorb fluid and activate toprovide hemostasis, as described further elsewhere herein. Optionally,as shown in FIG. 3E, once the sealant 2 is exposed within the puncture90, the advancer member 30 may be advanced to compress or tamp thesealant 2, e.g., against the positioning element 46. Optionally, theadvancer member 30 may include one or more markers 33, e.g., on oradjacent the proximal end 32, and the advancer member 30 may be advancedinto the puncture 90 a desired distance, which may be confirmed bymonitoring the markers 33. In addition or alternatively, the positioningmember 14 may include a second feature (not shown) over which theadvancer member 30 may pass when advanced a predetermined distance. Thesecond feature may provide an audible confirmation that the advancermember 30 has been advanced the predetermined distance (in addition orinstead of the visible confirmation provided by the markers 33). Inaddition, the second detent 41 b may ensure that the advancer member 30is not subsequently withdrawn once advanced the predetermined distance.

Once the sealant 2 has been exposed for sufficient time and/or tamped bythe advancer member 30, the positioning element 46 may be collapsed, andthe positioning member 14 withdrawn from the vessel 94 and puncture 90,e.g., pulling the collapsed positioning element 46 through the sealant 2and advancer member 30, as shown in FIG. 3F. The advancer member 30 maybe maintained substantially stationary during withdrawal of thepositioning member 14, e.g., to prevent migration and/or dislodgement ofthe sealant 2 within the puncture 90. Once the positioning member 14 iscompletely removed, the advancer member 30 may be removed from thepuncture 90, leaving the sealant 2 within the puncture 90, as shown inFIG. 3G.

Optionally, after removing the positioning member 14, liquid hydrogel orother sealing compound, or other material may be delivered into thepuncture 90, e.g., above and/or around the sealant 2, to assist inachieving hemostasis. For example, such material may be delivered viathe lumen 36 of the advancer member 30 and/or by introducing anotherdelivery device (not shown) into the puncture 90, e.g., after removingthe advancer member 30.

With additional reference to FIG. 1, with the freeze-dried hydrogelproximal section 4 of the sealant 2 delivered o the puncture 90 adjacentvessel 94, hydration may occur substantially immediately as the sealant2 is exposed from the tubular member 20 and begins to uptake localfluids (blood or interstitial fluids). For example, the proximal section4 of the sealant 2 may begin to swell rapidly such that the swelling andthe increase in the radial dimension of the proximal section 4substantially fills a portion of the available space in the puncture 90above the vessel 94, e.g., above the arteriotomy in the vessel wall. Theend result is a discrete, optimally targeted deposition of hydrogelsealant 2 that provides a seal over the arteriotomy.

In addition, the non-freeze-dried distal section 6 of non-cross-linkedprecursors absorbs local fluids, which initiates cross-linking in-situand results in a more secure mechanical hold on the surrounding tissueas the freeze-dried hydrogel conforms to the spaces in the tissue tract.Optionally, if the sealant 2 includes salts or other pH adjustingagents, exposure of the sealant 2 may dissolve the agent(s) in the localfluids, which may enhance or facilitate cross-linking of the precursors.

In an exemplary embodiment, if the sealant 2 is compressed against thearteriotomy over the vessel 94, the distal section 6 may bond to theouter surface of the vessel wall 96 and/or other tissue adjacent thearteriotomy, or may fill or otherwise penetrate into the arteriotomy,e.g., optionally extending into the interior of the vessel 94, which mayenhance the resulting seal and/or prevent migration of the proximalsection 4 of the sealant 2, e.g., away from the arteriotomy and vesselwall 96. Thus, the end result may be a discrete, optimally targeteddeposition of hydrogel sealant that provides a durable seal over orwithin the arteriotomy, as shown in FIG. 3G.

Several alternative embodiments of sealants are shown in FIGS. 4-11 anddescribed below that may be delivered, e.g., using the apparatus andmethods described elsewhere herein and/or in the references incorporatedby reference herein. The sealants described below may be formed from anyof the materials and methods described above for sealant 2.

For example, turning to FIGS. 4A and 4B, an exemplary embodiment of asealant 102 is shown that includes a proximal section 104 offreeze-dried hydrogel and a distal section 106 of non-cross-linkedprecursors, generally similar to other embodiments herein. In anexemplary embodiment, uncoated biomaterial, e.g., freeze-dried hydrogel,may be rolled or otherwise formed, similar to other embodimentsdescribed herein, for the proximal section 104. Thus, the sealant 102may include a lumen (not shown) extending longitudinally between theproximal and distal sections 104, 106, e.g., to allow delivery of thesealant 102 over a positioning member 40, similar to other embodimentsherein.

As shown in FIG. 4A, a cylindrical plug or bolus 106 of substantiallydry non-cross-linked hydrogel precursors may be fused or otherwiseprovided on or adjacent the distal end of the proximal section 104. Forexample, the distal section 106 may be a solid mass or plug, e.g., amelted and solidified form attached to the proximal section 104, similarto the processes described above. Alternatively, the distal section 106may be a bolus of powder provided adjacent but separate from theproximal section 104, e.g., sintered or otherwise compressed together,while remaining in a powder form, or simply loaded into a deliverycartridge distal to the proximal section 104 such that the powder isreleased when the sealant 102 is delivered from the cartridge. Forexample, if the precursor powder is sintered into a desired shape, thepowder particles may behave as a solid mass yet may easily separate fromone another, e.g., when delivered within a puncture, which may increasesurface contact between the powder and physiologic fluids, which mayaccelerate and/or otherwise enhance cross-linking of the precursors.

Optionally, the non-cross-linked precursors of the distal section 106and/or the uncoated biomaterial of the proximal section 104 may havesalts or other pH adjusting agents impregnated therein or appliedthereto such that, when physiological fluids wet the biomaterial and/orunreacted hydrogel precursors, a favorable pH may be obtained forcross-linking the distal section 106. The ratio of the lengths ofunreacted hydrogel precursors to uncoated biomaterial, i.e., distal toproximal sections 106, 104, may range from 0-100% for the respectivematerials, and the length of the overall sealant 102 may vary, similarto other embodiments herein.

During use, the sealant 102 may be advanced into position, e.g., over apositioning member 40 and/or towards a positioning element 46, inapposition to the surface 96 of an artery at the arteriotomy within apuncture (not shown), e.g., using apparatus and methods similar to thosedescribed elsewhere herein. The local fluids within the puncture mayinitiate cross-linking of the precursors of the distal section 106,which may cause the cross-linking precursors to soften, flow intoavailable space within the puncture, e.g., into the arteriotomy and/orinto the vessel itself, and begin to cross-link to form a hydrogel. The“setting” action of the non-cross-linked precursors as the in-situcross-link occurs may act as a glue to substantially fix the sealant 102in position over the arteriotomy.

The distal section 106 may also form a patch over the arteriotomy, e.g.,against or into the vessel wall 96, e.g., with the sealant 102 acting asa sponge to absorb any blood in the immediate area, e.g., to minimizesubsequent oozing. For example, as shown in FIG. 4B, the distal section106 may be compressed against the vessel wall 96, e.g., using a tampingmember (not shown), similar to other embodiments herein, which may causedeformation of the cross-linking precursors, potentially enhancing thecoverage area of the adherent material and/or increasing the surfacearea for the cross-linking reaction.

Turning to FIGS. 5A and 5B, an alternative embodiment of a sealant 102′is shown that includes a proximal section 104′ and a distal section 106′generally similar to the sealant 102 of FIGS. 4A and 4B. However, asshown in FIG. 5A, unlike the previous embodiment, the proximal section104′ may include a pocket 104 d ′ formed in the distal end of theuncoated biomaterial within which the non-cross-linked precursors of thedistal section 106′ may be formed or deposited. For example, a solidmass of non-cross-linked precursors or a bolus of precursor powders maybe loaded into the pocket 104 d, e.g., loosely or fused to the distalend of the first section 104 a,′ similar to previous embodiments.

As shown in FIG. 5B, the sealant 102′ may be compressed within apuncture and/or against an arteriotomy in the vessel wall 96, similar toother embodiments herein, which may cause an annular wall of the firstsection 104′ defining the pocket 104 d′ to splay out over the flatteneddistal section 106,′ e.g., providing improved adhesion between theuncoated biomaterial of the proximal section 104′ and the adherentmaterial of the distal section 106.′

Turning to FIGS. 6A-6C, another alternative embodiment of a sealant 102″is shown, similar to the sealant 102′ of FIGS. 5A and 5B (or the sealant102 of FIGS. 4A and 4B) including a proximal section 104″ offreeze-dried hydrogel and a distal section 106″ of non-cross-linkedpolymers. Similar to the sealant 102,′ the proximal section 104″includes a pocket 104 d″ for receiving the non-cross-linked precursorsof the distal section 106.″ Unlike the previous embodiments, theproximal section 104″ may include one or more longitudinal slits 104 e″formed laterally through the uncoated biomaterial and extending onlypartially between and spaced apart from the proximal and distal ends ofthe proximal section 104.″ Such a slit 104 e″ through the side of theproximal section 104″ may facilitate collapsing the sealant 102″ duringcompression, e.g., into a “lantern” shaped body, as shown in FIGS. 6Band 6C. For example, these drawings show how compression may result in asubstantially flattened low profile for the delivered sealant 102,″which may provide maximum surface area coverage against the vessel wall96.

Turning to FIGS. 7A and 7B, still another embodiment of a sealant 202 isshown that includes two distinct sections of sealant material. Thedistal section 204 may be formed from a relatively softer, rapidlyswelling composition, e.g., freeze-dried hydrogel, while the proximalsection 206 may be formed from a relatively harder, slower swellingcomposition. As shown, the proximal section 206 may be nested to somedegree into the distal section 204, e.g., including a tapered distal tip206 f that is initially provided within a similar shaped pocket 204 inthe proximal end of the distal section 204, as shown in FIG. 7A.

The act of placing a compressive load on the proximal section 206 of thesealant 202 while holding the distal face of the distal section 204substantially fixed (e.g., in this case using a balloon 46 as abackstop), may drive the proximal section 206 into the distal section204. As shown in FIG. 7B, this action may expand the distal section 204into a shape that is wider than its original configuration. For example,as shown in FIG. 7B, the distal section 204 may be designed to splitduring compression, bulge, or otherwise deform under the compressiveload.

Turning to FIGS. 8A-8C, still another embodiment of a sealant 304 isshown that includes a proximal end 304 a, a distal end 304 b and alongitudinal slit 304 e extending partially between the proximal anddistal ends 304 a, 304 b, e.g., similar to the proximal section 104″ ofthe sealant 102″ of FIGS. 6A-6C. In this embodiment, the freeze-driedhydrogel or other sealant may include one or more slits to enable acontrolled deformation of the sealant 304 under a compressive load. Forexample, the sealant 304 may include two longitudinal slits 304 e (onlyone visible in the side view shown in FIG. 8A), e.g., offset one hundredeighty degrees (180°) apart from one another around the circumference ofthe sealant 304. Alternatively, the number and/or orientation of theslits 304 e may be modified, e.g., to attain a desired morphology aftercompression.

It will be appreciated that the shape of any of the sealants herein maybe modified to have a shape that is conducive to controlled deformation.Examples include an inverted golf tee, an hourglass, swept or wavysurfaces, and the like.

Turning to FIG. 9, additional alternative embodiments of sealants areshown that include non-cross-linked precursor sections 406 a-406 g andfreeze-dried hydrogel main sections 404 a-404 g. The location of thenon-cross-linked precursors 406 a-406 g may be proximal to, distal to,or both proximal and distal to the hydrogel main sections 404 a-404 g.The precursors 406 a-406 g may be provided as a solid mass fused orotherwise attached to the main section 404 a-404 g or as a bolus ofpowder, similar to other embodiments herein. For example, a sealant 402a may be provided that includes precursor sections 406 a within pocketsin both proximal and distal ends of the main section 404 a, while thesealant 402 b may include a precursor section 406 b within a pocket onthe proximal end of the main section 404 b.

Sealants 402 c and 402 d include a main section 404 c, 404 d, e.g.,formed from freeze-dried hydrogel, and non-cross-linked precursorsections on either both ends 406 c or one end 406 d of the main section404 c, 404 d. In these embodiments, the non-cross-linked sections 406 c,406 d may be a solid mass fused to the main sections 404 c, 404 d or abolus or sintered mass of precursor powders.

Sealants 402 e-402 g include main sections 404 e-404 g, e.g., formedfrom freeze-dried hydrogel, and distal sections 406 e-406 g, e.g., solidmasses of non-cross-linked precursors fused or otherwise attached to themain sections 404 a-404 g. For example, in sealant 402 e, the mainsection 404 e may include a recess, e.g., a conical recess in one endfor receiving the distal section 406 e substantially flush with the endof the main section 404 e. Alternatively, the distal section 406 f mayextend from the recess in the main section 404 f, as shown for thesealant 402 f. In a further alternative, the sealant 402 g includes asmaller tab or other feature extending from the main section 404 garound which the distal section 406 g may be formed and/or extend.

Turning to FIGS. 10A-10D, another embodiment of a sealant 502 is shown,which may include a section of rolled hydrogel or other base material504, such as any of the materials described above, including proximaland distal ends 504 a, 504 b. A plurality of slits 504 h may be formedin the distal end 504 b, e.g., by mechanical cutting, laser cutting,stamping, and the like, as shown in FIG. 10A. The distal end 504 b maythen be coated, e.g., with non-cross-linked precursors 506, as shown inFIG. 10C, similar to other embodiments herein and in the referencesincorporated by reference herein. Optionally, pH controlling salts andthe like may be embedded in the coating or in the non-coatedbiomaterial, e.g., as shown in FIG. 10B. The slits 504 h may facilitatecollapsing the coated end 504 b of the sealant 502, e.g., resulting in awider footprint to cover an arteriotomy or other vessel puncture, asshown in FIG. 10D. The sealant 502 may be delivered using apparatus andmethods similar to those described elsewhere herein.

Turning to FIGS. 11A and 11B, an exemplary embodiment of a pliablepatch-like material 602 is shown, e.g., having lateral dimensions (fromthe perspective of FIG. 11A), e.g., a width, height, diameter, and thelike depending on the desired shape for the patch, formed from materialwith minimal stretch in the lateral directions. The patch 602 mayinclude a weave or other arrangement 605 of synthetic biocompatibleand/or bioabsorbable fibers, such as PLG, PLA or PGA, e.g., defining afirst or base layer, as shown in FIG. 11B. Alternatively, the patch 602may also be formed from naturally occurring proteins, such as collagen,or other bioabsorbable materials, such as those described above.

As shown in FIG. 11B, the patch 602 may be covered on one or both sideswith non-cross-linked precursors, similar to other embodiments herein,e.g., to provide an adhesive layer 606 for the patch 602. As shown, thecoating 606 has been provided on only the bottom side of the base layer605 of the patch 602. In the case of coating 606 on only one side, alayer 604 of freeze-dried hydrogel or other expandable, bioabsorbablematerial may be provided on the top side of the base layer 605, e.g., toabsorb excess fluid and/or expand to fill a space above the deliverysite. Optionally, salts to control the pH (not shown) may be blendedwith the coating 606, embedded in the base material 605, embedded in thefreeze-dried hydrogel 604, and/or dissolved in a buffer solution that isused to saturate the assembly immediately before or after the patch 602is applied to a arteriotomy or other issue surface.

The patch 602 may be delivered using the apparatus and methods describedelsewhere herein, e.g., where the patch 602 is small enough to be loadedinto a cartridge. Alternatively, the patch 602 may be applied manually,e.g., if the tissue surface is sufficiently exposed.

For example, upon application to a vessel or other tissue surface orstructure, e.g., over an arteriotomy or other puncture (not shown),adhesion to the vessel may occur due to the coating 606, but thenon-stretch nature of the base layer 605 of the substrate patch 602 mayprevent the expanding pressurized vessel from substantially opening orenlarging the arteriotomy because of the lateral resistance of the patch602 to expansion. The dense weave of the base layer 605 and thecross-linking of the coating 606 may prevent blood or other fluid fromthe vessel from leaking though the patch 602. The size of the patch 602may vary from being large enough to surround all or a portion of vesselhaving a puncture therethrough, e.g., adhering the patch all around thepuncture to only pulling together the mid-point of the vessel puncturefor achieving substantial hemostasis. Optionally, after applying thepatch, another hemostatic material, such as freeze-dried hydrogel (orany other sealant, such as those described elsewhere herein) may beapplied over the top to achieve complete hemostasis.

In still another embodiment, a plurality of coated sealant pellets (notshown) may be provided for sealing a puncture through tissue. Forexample, freeze-dried hydrogel sealant may be used as a carrier fornon-cross-linked PEGs or other precursors in a solid (i.e., melted,mixed, and solidified) form, e.g., a solid shell surrounding theunderlying freeze-dried hydrogel. For example, freeze-dried hydrogelsealant may be punched, ground, or other formed into particles, e.g.,having one or more diameters between about 0.5-10 millimeters. Theparticles may then be spray-coated with a hot liquid mass, e.g.,including the melted PEG amine and PEG ester. The resulting pellets maythen be delivered over an arteriotomy, into a puncture, or applied to atissue surface, e.g., as a bolus through a sheath or other deliverydevice, and the non-cross-linked precursors may reconstitute and bind toform a slurry of adhesive gel and rapidly-absorbing hydrogel sealantover the arteriotomy, within the puncture, and/or onto the tissuesurface.

It will be appreciated that elements or components shown with anyembodiment herein are merely exemplary for the specific embodiment andmay be used on or in combination with other embodiments disclosedherein.

While the invention is susceptible to various modifications, andalternative forms, specific examples thereof have been shown in thedrawings and are herein described in detail. It should be understood,however, that the invention is not to be limited to the particular formsor methods disclosed, but to the contrary, the invention is to cover allmodifications, equivalents and alternatives falling within the scope ofthe appended claims.

1-40. (canceled)
 41. A sealant for sealing a puncture through tissue,comprising: a mass of PEG precursors comprising PEG-ester precursors andPEG-amine precursors, the PEG-amine precursors including a free-amineform of PEG-amine precursors and a salt form of PEG-amine precursors;wherein the sealant is provided such that the free-amine form ofPEG-amine precursors are at least partially cross-linked with thePEG-ester precursors, and the salt form of PEG-amine precursors remainin an unreactive state until exposed to an aqueous physiologicalenvironment, whereupon the salt form of PEG-amine precursors undergoin-situ cross-linking with the PEG-ester precursors to provide adhesionto tissue adjacent the puncture.
 42. The sealant of claim 41, wherein aratio of active group sites of PEG-ester precursors/salt form ofPEG-amine precursors/free-amine form of PEG-amine precursors is betweenabout 50/42/8 and 50/48/2.
 43. The sealant of claim 41, wherein a ratioof active group sites of PEG-ester precursors/salt form of PEG-amineprecursors/free-amine form of PEG-amine precursors is between about60/32/8 and 60/38/2.
 44. The sealant of claim 41, wherein a ratio ofactive group sites of PEG-ester precursors/salt form of PEG-amineprecursors/free-amine form of PEG-amine precursors is between about50/45/5 and 70/25/5.
 45. The sealant of claim 41, wherein a ratio ofactive group sites of PEG-ester precursors/salt form of PEG-amineprecursors/free-amine form of PEG-amine precursors is about 60/35/5. 46.The sealant of claim 41, wherein a ratio of active group sites of thePEG-ester precursors to the PEG-amine precursors is at least aboutone-to-one (1:1).
 47. The sealant of claim 41, wherein the sealant isable to withstand higher pressures as compared to a comparison sealant,wherein the mass of PEG precursors in the comparison sealant comprisesPEG-ester precursors and a salt form of PEG-amine precursors, but doesnot include a free-amine form of PEG-amine precursors.
 48. The sealantof claim 41, wherein the sealant has a substantially uniform outercross-section between about one and eight millimeters (1-8 mm).
 49. Thesealant of claim 41, wherein the mass of PEG precursors comprises asubstantially uniform plug of PEG precursors.
 50. The sealant of 41,wherein the sealant comprises a first section and a second section, thefirst section comprising a freeze-dried hydrogel that expands whenexposed to physiological fluid within the puncture and the secondsection comprising the mass of PEG precursors fused to the freeze-driedhydrogel.
 51. The sealant of claim 50, wherein the first sectioncomprises a sheet rolled into a tubular shape, thereby defining a lumenextending along a length of the freeze-dried hydrogel, and wherein thesecond section comprises a passage therethrough aligned with the lumen.52. The sealant of claim 50, wherein the first section has a lengthbetween about one and twenty millimeters (1-20 mm), and the secondsection has a length that is substantially shorter than the length ofthe first section.
 53. The sealant of claim 50, further comprising atransition zone between the first section and the second section,wherein PEG-precursors of the second section permeate into an end of thefirst section to form the transition zone.
 54. The sealant of claim 50,wherein the first section forms a proximal section of the sealant andwherein the second section forms a distal section of the sealant. 55.The sealant of claim 50, wherein the sealant is provided in an apparatusfor sealing a puncture extending through tissue, the apparatuscomprising: a tubular member comprising a proximal end, a distal endsized for insertion into the puncture, a lumen extending between theproximal end and the distal end, and a distal opening in communicationwith the lumen; and wherein the sealant is disposed within the lumen ofthe tubular member such that the second section of the sealant isdisposed closer to the distal opening of the tubular member than thefirst section.
 56. A method for sealing a puncture extending throughtissue, comprising: introducing a sealant into a puncture, the sealantcomprising a mass of PEG precursors comprising PEG-ester precursors, afree-amine form of PEG-amine precursors, and a salt form of PEG-amineprecursors, wherein the free-amine form of PEG-amine precursors are atleast partially cross-linked with the PEG-ester precursors, and the saltform of PEG-amine precursors remain in an unreactive state; exposing thesealant to fluid within the puncture, whereupon the salt form ofPEG-amine precursors undergo in-situ cross-linking with the PEG-esterprecursors to provide adhesion to tissue adjacent the puncture.
 57. Themethod of claim 56, wherein the sealant is able to withstand higherpressures as compared to a comparison sealant, wherein the mass of PEGprecursors in the comparison sealant comprises PEG-ester precursors anda salt form of PEG-amine precursors, but does not include a free-amineform of PEG-amine precursors.
 58. The method of claim 56, wherein thesealant further comprises a freeze-dried hydrogel, wherein the mass ofPEG precursors is fused to the freeze-dried hydrogel, and wherein themass of PEG precursors enters the puncture before the freeze-driedhydrogel when introducing the sealant into the puncture.
 59. A methodfor making a sealant, comprising: forming an elongate first sectionhaving a cross-section sized for delivery into a puncture throughtissue; melting a mixture of PEG precursors comprising PEG-esterprecursors, a free-amine form of PEG-amine precursors, and a salt formof PEG-amine precursors; and fusing the mixture of PEG precursors ontoan end of the first section, wherein the free-amine form of PEG-amineprecursors at least partially cross-links with the PEG-ester precursors,and the salt form of PEG-amine precursors remain in an unreactive stateuntil exposed to an aqueous physiological environment.
 60. The method ofclaim 59, wherein fusing the mixture of PEG precursors onto the end ofthe first section comprises: using a vacuum to apply the mixture of PEGprecursors onto the end of the first section, and allowing the mixtureof PEG precursors to cool and solidify into a solid mass fused to theend of the first section.